Highly active antiretroviral therapy (HAART) has been linked to increased risk of chronic medical conditions, from cardiovascular complications to autoimmune diseases. We have recently found that use of HAART is independently associated with worse airway obstruction. The overall goal of this project is to investigate the hypothesis that immune restoration through HAART leads to increased airway obstruction/chronic obstructive pulmonary disease via propagation of a chronic inflammatory response to pulmonary pathogens and/or autoantigens. We will study the effects of HAART initiation through a prospective longitudinal study of HIV outpatients at the University of Pittsburgh, as well as through an analysis of specimens archived as part of the Multicenter AIDS Cohort Study and the Women's Interagency Study. Research Aims: (1) To test the hypothesis that HAART initiation is associated with increased airway obstruction and/or emphysema. (2) To test the hypothesis that initiating HAART induces a "modified immune restoration syndrome," creating a pro-inflammatory environment in response to an underlying pathogen and/or through unmasking of autoantigens. (3) To test the hypothesis that development of a chronic inflammatory response, either in response to Pneumocystis or autoantigens, is associated with increased airway obstruction and/or emphysema. Career Goals: This research proposal presents a comprehensive plan by which the P.I. will help determine pathophysiologic mechanisms connecting HAART and COPD and will also achieve the following: 1. Broaden the candidate's ability to perform clinical/translational studies through the experience of conducting a prospective longitudinal study;2. Increase the candidate's analytical techniques in statistical analysis and modeling;and 3. Transform the candidate into a leading independent investigator in HIV-associated pulmonary disease through intensive didactics, conferences, and research experience. ! PUBLIC HEALTH RELEVANCE: This proposal represents a major step in determining the impact of HAART and immune restoration on the development of COPD and will provide a crucial foundation for future studies of HIV-related chronic lung disease. Given the increasing numbers of aging HIV-infected subjects with prolonged exposure to HIV and HAART, this study will provide important information for care and treatment of these patients.